The use of cocaine in the US remains a serious and costly epidemic. The search of an effective treatment for cocaine addiction is mandatory, and has been considered a major goal of the National Institute on Drug Abuse. Since a highly efficacious pharmacological treatment has not yet been demonstrated, the search for a better understanding of the mechanisms underlying cocaine abuse is a high priority. Increased dopaminergic neurotransmission, through the inhibition of the dopamine transporter (DAT), has been suggested to mediate reinforcing/addictive properties of cocaine in animals and humans. The recently developed transgenic mouse lacking the DAT (DAT knockout mouse) offers the unique opportunity to determine the role of this transporter in the initiation and maintenance of cocaine taking behavior. The results from this proposal will provide insights into the design of new drugs for treating cocaine addiction, therefore with high impact on public health. This grant proposal is to test the hypothesis that the DAT is necessary to control cocaine self-administration. This hypothesis will be tested through a series of experiments having the following aims: 1. characterization of the role of the DAT in behavioral factors, such as locomotor activity and environmental habituation, that may directly influence the learning of operant behavior and initiation (acquisition) of intravenous (IV) cocaine self-administration. This will be accomplished by testing the effect of periods of habituation and/or food-shaping in the acquisition of IV cocaine self-administration in DAT knockout mice and wild-type. 2. characterization of the role of the DAT in the cocaine self-administration acquisition potency. This will be accomplished by testing the effect of different doses of cocaine in the acquisition of cocaine self-administration in DAT knockout mice and wild-type. 3. characterization of the role of the DAT in the maintenance of cocaine taking behavior. This will be accomplished by testing the effect of different doses of cocaine in the cocaine self-administration, in a fixed ratio (FR) schedule, in DAT knockout mice and wild-type mice. 4. characterization of mechanism(s) underlying cocaine maintaining responding in DAT knockout mice. This will be accomplished by testing the effect of dopamine (DA) D1 receptor selective antagonist SCH39166, the DA D2 receptor selective antagonist eticlopride, the serotonin (5- HT) uptake blocker fluoxetine, and the norepinephrine (NE) uptake blocker nisoxetine in the cocaine self-administration in DAT knockout and wild-type mice. 5. characterization of the role of the DAT in the reinforcing efficacy of cocaine and other drugs of abuse, such as heroin, and in the reinforcing efficacy of non-drug reinforcers, such as food. This will be accomplished by testing DAT knockout and wild- type mice in cocaine, heroin or food self-administration in a progressive ratio (PR) schedule of reinforcement.